The Urinary Tract

Kidney: Chronic Kidney Disease

Dr. Mohammed I. Malki

Assistant Professor of Pathology
College of Medicine, Qatar University
Annex Building, Office 129A
momalki@qu.edu.qa
Content

➢ Chronic kidney disease ➢ Diseases Involving Blood Vessels

• Definition • Malignant Hypertension
• Pathophysiology • Thrombotic Microangiopathies
• Stages
• Morphology
• Clinical presentation
 Chronic Kidney Disease (CKD)

➢ Either kidney damage or a decreased glomerular filtration rate (GFR) of less than
60 mL/min/1.73 m2 for at least 3 months
➢ End stage kidney failure result of progressive scarring from any type of kidney
disease
• Glomeruli, tubules, interstitium and vessels are sclerosed
➢ Most common causes:
• Diabetes (up to 50%)
• Hypertension (up to 30%)
• Glomerular diseases
• Urinary tract obstruction
➢ Treatment:
• Dialysis or Transplantation
 Chronic Kidney Disease (CKD)

Criteria for CKD (either one of the following criteria must be present for > 3 months)

➢ Marker of Kidney Damage (One or more)

• Albuminuria: ( urine ACR > 3 mg/mmol or 24 hours urine albumin >30 mg/24 hours)
• Hematuria: urine sediment abnormalities (RBC cast, etc.)
• Electrolyte abnormalities due to renal tubular disorders (RTA, Fanconi syndrome,
etc.)
• Abnormalities detected on histopathology (GN, TIN etc.)
• Structural abnormalities detected on imaging (Cysts, Scar, etc.)
• History of kidney transplant

Or

➢ Decrease GFR: GFR < 60 ml/min/1.73 m2 with or without kidney damage

 CKD - Pathogenesis
Hypertension

➢ Glomerular and vascular changes:

❑ Elevated systemic blood pressures cause a hypertrophic response leading to intimal thickening
of the large and the small vasculature
❑ The mechanisms are compensatory at first, but later lead to glomerular damage
▪ Global sclerosis – ischemic injury to the nephrons causes death
▪ Focal segmental sclerosis – glomerular enlargement for compensation of the loss of
nephrons in other areas of the kidney

➢ Interstitial nephritis:
❑ The vascular and glomerular disease lead to tubular atrophy and an intense chronic interstitial
nephritis

➢ Chronically these changes lead to tubular and glomerular loss causing nephrons loss
▪ With the death of some nephrons, less are available to maintain the GFR
▪ Gradual decline in the GFR is noticed as the nephrons continue to die
 Malignant Hypertension (blood vessels)

➢ Blood pressure usually greater than 200/120 mm Hg

➢ Occurs in about 5% of hypertensive individuals in USA

➢ Higher in developing countries

➢ It may arise de novo (i.e., without preexisting

hypertension), or it may appear suddenly in an individual
who had mild hypertension

➢ Pathogenesis:
 Malignant Hypertension

Morphology

➢ Fibrinoid necrosis:
▪ Formation of pink fibrin of small renal arteries

➢ Hyperplastic arteriolosclerosis
▪ Homogeneous, granular eosinophilic appearance
▪ Proliferation of intimal cells after acute injury produces Fibrinoid necrosis of small renal arteries
an onion-skin appearance
▪ Marked narrowing of interlobular arteries and larger
arterioles (obliteration)
▪ Necrosis also may involve glomeruli as well as
arterioles

Hyperplastic arteriolosclerosis (onion-skin lesion)

 Malignant Hypertension

➢ Clinical Features:

❑ Papilledema, encephalopathy, cardiovascular abnormalities, and renal failure

❑ Early symptoms (increased intracranial pressure )

▪ Headache, nausea, vomiting, and visual impairment, particularly the development of
scotomas, or “spots” before the eyes

❑ Renal Manifestations
▪ Marked proteinuria and hematuria but no significant alteration in renal function

❑ Present with severe acute kidney injury and renal failure

 CKD - Pathogenesis

➢ Diabetes
CKD - Pathogenesis

Light photomicrographs illustrating various stages of developing

glomerular lesions and tubulointerstitial disease in diabetic
nephropathy.
(a) A normal glomerulus

(b) Thickened basement membranes (arrowheads) and expanded

mesangial regions (asterisks)

(c) The nodular appearance of the mesangial regions characteristic of

Kimmelstiel-Wilson lesions (asterisks)

(d) The tubulointerstitial lesions include thickened tubular basement

membrane (TBM), hyalinization of afferent arteriole (ART), and
fibrosis of the interstitium (INT).

Abbreviations: c, capillary lumen; En, endothelial cell; Ep, visceral

epithelial cell (podocyte); Me, mesangium; US, urinary space.
CKD - Pathogenesis
CKD – Stages
 CKD – Morphology

Gross - Features:

➢ Kidneys are symmetrically contracted

➢ Damage in blood vessels or glomeruli

▪ Kidney surface: red-brown and
diffusely granular

➢ Damage by chronic pyelonephritis

▪ Uneven kidney with deep scare
CKD – Morphology

Microscopically - Features:

▪ Glomerular Sclerosis

▪ Interstitial fibrosis with Lymphocytic infiltrates

▪ Tubules atrophy

▪ Loss of portions of the peritubular capillary network

▪ Arteries (small/medium size)

▪ Thick walled
▪ Narrowed lumina
CKD – Morphology

The cortex is fibrotic, the glomeruli are sclerotic,

there are scattered chronic inflammatory cell
infiltrates, and the arteries are thickened. Tubules
are often dilated and filled with pink casts and give
an appearance of "thyroidization."
CKD – Morphology

Chronic glomerulonephritis: A Masson

trichrome preparation shows complete
replacement of virtually all glomeruli by
blue-staining collagen.
 CKD – Clinical Presentations

❑ Asymptomatic in stage 1-3 with GFR > 30ml/min

❑ Symptomatic in stage 4-5 with GFR < 30ml/min
➢ Early signs:
▪ Polyuria/oliguria, Hematuria, Edema
➢ Late signs:
▪ Hypertension
▪ Signs of anemia (pallor)
▪ Signs of Uremia:
• Brain (uremic encephalopathy): low
concentration, confusion, lethargy, asterixis,
coma
• Heart: pericarditis
 CKD – Clinical Presentations

• GIT: nausea & vomiting, anorexia, diarrhea

• Reproductive system: erectile dysfunction, decreased libido, amenorrhea
• Blood system: platelet dysfunction with tendency to bleed, infections due to WBCs
dysfunction
• Peripheral neuropathy: numbness, paraesthesia, restless leg syndrome
• Skin: dry skin, pruritus, ecchymosis
• Others: fatigue, hiccups, muscle cramps
CKD – Pathophysiological Changes
Sign/lab finding Symptoms Mechanism
Generalized edema Swelling Water retention due to a loss of GFR leading to sodium
and fluid retention. Fluid moves into the extravascular
space, due to increased hydrostatic pressure, causing
pitting edema in the lower extremity (fluid movement
could also be due to hypoalbuminemia, in some
diseases, leading to a low oncotic pressure)
Pulmonary crackles Shortness of breath Fluid accumulation causes pulmonary edema and loss of
air space causing ventilation-perfusion mismatch. This
leaves less area for oxygen diffusion form the blood
vessels
Anemia Fatigue, reduced exercise capacity, Erythropoietin (EPO), the major erythropoiesis
and pallor stimulator, is released from the kidneys; with renal
failure, there is loss of EPO release
Weight loss Loss of lean body mass Protein-energy malnutrition due to metabolic acidosis.
Loss of kidney function results in impaired H+ secretion
from the body
Hyperkalemia Malaise, palpitations Inability of the kidneys to secrete potassium in the urine
leads to life threatening arrhythmias
 CKD – Pathophysiological Changes

Sign/lab finding Mechanism

Mechanisms of renal osteodystrophy
Hyperphosphatemia Damaged kidneys fail to excrete phosphate
Also secondary to high parathyroid hormone levels
Hypocalcemia Thought to be secondary to low Vitamin D3 levels. In early stages of CKD, low levels
of calcitriol are due to hyperphosphatemia (negative feedback). In the later stages of
CKD, low levels are hypothesized to be due to decreased synthesis of 1α-hydroxylase
(enzyme that converts calcifediol to calcitriol in the kidneys)
Secondary and tertiary To compensate for the low calcium due to low Vitamin D levels, the parathyroid
hyperparathyroidism glands increase the parathyroid hormone secretion. This leads to a high bone
turnover, always attempting to normalize the low calcium levels in the blood. Over
time, this becomes maladaptive leading to extraosseous calcification, and
parathyroid hyperplasia develops (tertiary hyperparathyroidism)
 CKD – Pathophysiological Changes

Sign/lab finding Symptoms Mechanism

Complications of uremia
Urea and other toxins accumulate in the blood and cause life threatening issues.

Ecchymosis, GI bleeding Increased tendency to bleed and Uremia-induced platelet dysfunction

ecchymosis

Pericardial friction rub Chest pain, malaise Uremic pericarditis

Headaches, confusion, coma Uremic encephalopathy; adverse effects of urea

on the CNS (Mechanisms unclear)
 Blood Vessels – Thrombotic Microangiopathies
❑ Thrombotic microangiopathy (TMA) refers to lesions
seen in various clinical syndromes characterized by
microvascular thrombosis accompanied by
microangiopathic hemolytic anemia, thrombocytopenia,
and, in certain instances, renal failure

❑ 2 types:
➢ Primary TMA: shiga toxin–mediated hemolytic
uremic syndrome (HUS); atypical HUS, &
thrombotic thrombocytopenic purpura (TTP)

➢ Secondary TMA: Malignant hypertension &

scleroderma-associated TMA
 Blood Vessels – Thrombotic Microangiopathies
➢ Shiga toxin–mediated HUS:

❑ Intestinal infection with Shiga toxin–producing E. coli (contaminated ground meat) and infections with
Shigella dysenteriae type I

❑ Pathogenesis:

▪ At low doses: the toxin activates endothelial cells, leading to leukocyte adhesion, increased
endothelin production and decreased nitric oxide production (both favoring vasoconstriction), as well
as other changes that may promote platelet adhesion and activation

▪ At high doses: the toxin causes endothelial cell death

▪ All of these alterations may contribute to the formation of thrombi, which tend to be most prominent
in glomerular capillaries, afferent arterioles, and interlobular arteries
 Blood Vessels – Thrombotic Microangiopathies
➢ Atypical HUS:
❑ Genetic abnormalities in complement regulatory proteins (mostly factor H but also factor I and
membrane cofactor protein)
❑ Autoantibodies to complement regulatory proteins (anti–factor H or C5-9 membrane attack complex)
❖ Pathogenesis: excessive activation of complement, with ensuing microvascular injury and
microvascular thrombosis

➢ Thrombotic thrombocytopenic purpura (TTP):

❑ Genetic or acquired deficiency of a protease, ADAMTS 13, which cleaves multimers of von Willebrand
factor on the surface of endothelial cells
❑ As a result, formation of abnormally large vWF multimers that activate platelets spontaneously,
leading to platelet aggregation and thrombosis in multiple organs, including the kidney.
Recommended Resource

❑Robbin Basic Pathology (10th edition)

▪ Chapter 14, page 573.

❑Essential of Rubins Pathology (8th edition)

▪ Diabetic Glomerulosclerosis, page 933.
▪ Malignant Hypertension, page 617.

Thank You
Board Review Question

In a patient suspected to have diabetic kidney disease, what is the earliest structural
change in a kidney biopsy recognized by electron microscopy?

A. Deposits of randomly oriented nonbranching fibrils in the mesangium

B. Diffuse thickening of the glomerular basement membrane
C. Diffuse effacement of podocytes' foot processes
D. Electron dense subepithelial deposits
E. Expansion of the mesangial regions